Dialkyl sulfamyl benzoic acids



Patented Aug. 26, 1952 DIALKYL SULFAMYL BENZOIC ACIDS Charles S. Miller, Prospect Park, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Original application August- 20, 1949, Serial No. 111,584. Divided and this application May 18, 1950, Serial No. 162,811

This invention relates to sulfamyl-benzoic acids which are-efiective as adjuvants for use in conjunction withthe administration of penicillin to provide an increase in the blood plasma penicillin concentratio-niwith a given dose of penicillin, thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin for providing a given blood level, or permitting the less frequent administration of penicillin while maintainin a penicillin blood level adequate for bactericidal or bacteriostatic purpos'es. The invention also relates to the preparation of various dosage forms in which one or. more of the new compounds are incorporated for administration by various routes.

:BfiIjllcillin today is a well established therapeutic agentused in the treatment of bacterial, in particular, coccus infections. For internal use, it is commonly administered intravenously, or intramuscularly,-or orally. Where high blood levels are'required intravenous administration or administration by continuous venoclysis is used.

The major cause of the difficulties involved in attemptingto maintainadequate or high penicillin blood levels follows from the fact that substantially all of the penicillin in the blood is removed in a single circulation through the kidneys. Penicillin appears tobe almost quantitatively excreted from the blood by the epithelial cells of the tubules, at least within plasma concentrations which have been explored, with the result that itsrateof excretion from the blood stream is approximatelyfive timesthat of materials which are excreted by glomerular filtration alone, the tubular 'excretion accounting for about 80 (81) and the glomeruli about 2o (19) Various proposals have been made to overcome the difilculties due to the rapid elimination of penicillin, such as the administration of it in suspension in an oleaginous material, the mixture being administered by intramuscular injection. While this proposal is efiective in prolonging the time interval between injections, its disadvantage is that the penicillin is still excreted almost quantitatively when the blood passes through the renal system, and therefore does not permit the maintenance of high blood levels nor does it permitthe useof smaller quantities of penicillin to obtain a given blood level.

' The second proposal which has been made to provide for the reduction in the rate of excretion of penicillin has been to use, in conjunction with it, a material which, like penicillin, is selectively excreted by the tubules. By having the ratio of the added agent to the penicillin sufliciently 7 Claims. (Cl. 167-55) large, this concept provides for a substantial re-f duction in the rate of excretion of penicillin by the tubules and thus slows down its removal to a substantial extent. Various agents, including diodrast and hippuric acid, or derivatives or recursors. thereof, have been proposed. orused for this purpose. Such agents do not, however, seem to afford a solution to the problem of value except in extreme cases, because as the reduction in the rate of penicillin excretion is a reflection of the degree of overloading of the tubules with materials which they function to remove from the blood, it is necessary to maintain a very high concentration of the agent in the blood stream to afford a favorable partition ratio between the agent and the penicillin and, in addition, because the agents are themselves rapidly removed from the blood stream, it is necessary to administer them in large quantities to maintain the necessary high plasma concentrations. This presents an additional problem since in order to maintain the high concentration of these agents they must be administered intravenously as they are not well absorbed from the gastro-intestinal track.

The present invention is based upon the discovery that removal of penicillin from the blood stream by the kidney tubules can be effectively blocked by the adjuvants of this invention, having the general formula f j N-S Oz coon and their salts, wherein R and R1 respectively'are alkyl radicals; the alkyl radicals represented by R. and R1 having a combined total of at least five and no more than eight carbon atoms; and whereinthe carboxyl group is attached to the ortho-, meta-, or para-position of the benzene nucleus in relation to the sulfonyl radical. Sulfamylbenzoic acid derivatives wherein the carboxyl group is in para-position have been found to be particularly effective adjuvants, and within this group, those in whichthe alkyl radicals represented by R and Rihave a combined total of five or six carbon atoms, such as the para-(di n propylsulfamyl) -benzoic acid and paras (di-isopropylsulfamyl) -benzoic acid, I have been found to be outstandingly efiective in inhibiting the renal excretion of penicillin.

The sulfamyl benzoic acids of the invention. are relatively non-toxic, they are soluble in blood plasma and operate, when carried by the blood stream into contact with the tubules, to prevent their normal action in removing penicillin from the blood stream. The adjuvants themselves are 1 not excreted to any substantial extent by the per 100 cc., which is about the threshold value for agents such as p-aminohippuric acid or diodrast which inhibit tubular penicillin excretion by competition for the available tubular excretion capacity. The highly effective adjuvants of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc. to almost zero, so that the actual elimination of penicillin from the blood stream becomes sub-' stantially that resulting from glomerular filtration, that is, about one-fifth the normal rate (ignoring plasma binding). The adjuvants are also eliminated by the glomeruli. I

The adjuvants may be administered orally or, when dissolved in an aqueous solution, they may be administered intravenously or intramuscularly. This. last method has not yet proven desirable for single injections of the material, because in general, administration of more than 2 cc. per single injection intramuscularly is inadvisable, and the quantities of adjuvant desirable to use, i. e., 4 to 16 grams per day, are such as to make injection by this route impractical. However, the sulfamylbenzoic acids or their salts are well adapted for continuous intramuscular or subcutaneous clysis.

In general, oraladministration of the adju,

vants at the rate of 4 to 16 grams per day is adequate to suppress the rate oipenicillin excretion to an extent such that the blood level with a given dose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as much as four times the level obtained without the use of the adjuvant, and will permit either the use of a very much smaller quantity of penicillin to provide a given blood level, for example, permitting the penicillin doses I to be about one-fourth of those commonly used,

'or permitting the provision of penicillin blood levels several times as great as those obtainable with the administration of penicillin by the routes ordinarily used today.

The adjuvants of the invention or a suitable salt of any one of them may be administered in admixture with the penicillin, or separately therefrom. In any event, whether the adjuvant is administered in admixture with or separately from the penicillin, the quantity used should be such as to provide a concentration in the blood stream of adjuvant adequate to block, substantially the excretory mechanism of the tubules. Maximum efiect will be obtained with blood plasma concentrations of about 5 to 15 mg. per 100 cc., obtainable at dosage levels of about a to 16 grams per day orally and somewhat less than this intravenously. I

The adjuvants may be prepared .in any convenient dosage form, eitheralone or admixed with penicillin, such as in a compressed tablet,

, a dry filled capsule or a soft elastic capsule. It

is to be understood, of course, that other ingredients, such as binders, diluents, excipients,

antacid substances, or other inert or therapeutically active compounds may be incorporated into any selected dosage form along with the adjuvant or adjuvant plus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin. Similarly, the adjuvant and, if desired, the penicillin may be dispersed in an oleaginous base either alone or along with other suitable substances and filled into soft elastic capsules, or an aqueous solution may be prepared and filled into ampuls. Other suitable dosage forms will be readily apparent to thoseskilled in the art, and it is not the purpose of this discussion to limit the mode of packaging or administration to those specifically described herein.

The new sulfamyl benzoic acids of the invention wherein the carboxyl radical is in paraposition in relation to the sulfonyl radical on the benzene nucleus are generally made by first preparing a para-carboxybenzenesulfonyl halide by oxidation of para-toluenesulfonyl halide, or by preparing para-cyanobenzenesulfonyl halide by treating para-sulfamyl benzoic acid with phosphorus pentachloride. The para-carboxybenzenesulfonyl halide or para-cyanobenzenesulfonyl halide thus formed is reacted with the appropriate di-alkyl amine, advantageously using an excess, for example, two to three equivalents, of the amine, and when the cyanobenzenesulfonyl halide reactant is used, hydrolyzing the product thus formed to the corresponding-oarboxyl derivative. The reaction is preferably carried outv in the presence of a solvent, such as acetone or pyridine and the like, or in aqueous sodium hydroxide, and preferably with cooling. Any by-product formed during the reaction is removed by treating the reaction medium with a weak, alkaline substance, such as an aqueous sodium bicarbonate solution, filtering ofi the precipitated by-product, and then recovering the desired sulfamyl benzoic acid from the'filtrate by acidification.

It is possible in some instances to prepare the di-alkyl derivatives by alkylation of a monoalkylsulfamyl-benzoic acid, preferably in the presence of a solvent, such as in aqueous alkali.

The ortho-sulfamyl benzoic acid derivatives may be prepared by reacting saccharin with an alkyl halide, and treating the product thus formed with an alkali metal alcoholate to obtain the desired end product. I v

The meta-sulfamyl benzoic acid derivatives may be prepared by reacting meta-sulfobenzoyl dichloride with an alcohol, e. g. methanol, adding the product thus formed to the alkyl amine, preferably dissolved'in a solvent and advantageously" with cooling, thereby obtaining alkyl meta-(alkylsulfamyl)-benzoate. The ester is then hydrolyzed to the corresponding benzoic acid derivativeby known methods.

The preparation of the compounds of the invention is illustrated by, but not restricted to the following examples:

Example I .p- (Di-n-butylsulfamyl) -benzoic acid-To 38.7 grams (0.3 mole) of di-n-butylamine dissolved in 300 milliliters of dry acetone, contained in an open flask provided with a stirrer, 22.1 grams (0.1 mole) of p-carboxybenzenesulfonyl chloridewas added in portions with cooling and stirrin The reaction was stirred for one-half hour after which the suspension was concentrated over a steam bath to about one-third the original volume. The residue was poured into 250 milliliters of cold water, the solution'made acid with dilute hydrochloric acid, and the crude product removed by "filtration. The crude productwas dissolved in dilute sodium bicarbonate solution. The solution was treated with decolorizing charcoad and filtered. The product, after precipitation from the solution by an excess of dilute hydrochloric acid, was recrystallized from 50% aqueous alcohol. The yield was 20 grams (64%), M. P. 163-164.

Example II p (Dz' n propylsulfamyl) benzoic acid-24.0 grams (0,11 mole) of p-carboxybenzenesulfonyl chloride was added in small portions to a suspension of 20.0 grams (0.146 mole) of di-n -propylamine in 100 milliliters of sodium hydroxide with vigorous stirring at a. temperature of -25. Stirring was continued iorfifteen minutes after the final addition. The clear solution was treated with decolorizing carbon and filtered. The product was precipitated by the addition of anexcess of hydrochloric acid. The crude product was purified by reprecipitation from bicarbonate solution and recrystallization from dilute alcohol. The yield was 20.0 grams (64%) melting at 94196.

By replacing the di-n-butylamine of Example I or the di-n-propylamine of Example 11 by an equivalent amount of any other di-alkyl amine and following substantially the same procedure outlined in either example," the corresponding para-(di-alkylsuliamyl)-benzoic acids are obtained. Examples of other compounds prepared by these methods include those listed in Table A:

Table A N-sOZ-GCOOH r Yield, 1 R R percent M. P., o.

n-p ropyl n-propyl 51 193495 isobutyl isobutyl l7 ZOO-201.5

poured into 50 cc. of concentratedhydrochloric acid and 500 grams of crushed ice. A dark oil precipitated which soon solidified. The solid was removed by filtration and air-dried, yielding 22.5 grams (75%) of p-(di-sec-butylsulfamyl)- benzonitrile, melting at 88-791". After repeated recrystallizations from isopropyl ether, the nitrile melted at 97-99". grams (0.68 mole) of the crudenitrile was heated in 150 milliliters of 10% sodium hydroxide under reflux until no more ammonia was evolved (approximately four hours). The solution was treated with clecolorizing carbon, and filtered and the product precipitated from the filtrate with an excess. of hydrochloric acid. The p-(di-sec-butyilsulfarnyl)- benzoic acid thus obtained was dissolved in dilute sodium bicarbonate solution and reprecipitated with dilute hydrochloric acid. The yield was 14 grams of product; M. P. 175-179". Three recrystallizations from dilute alcohol gave 7.5 grams (18%) of product; M. P. 185.

By replacing the di-secondary butylami'ne of Example III by any other di-alkylaminexand following substantially the same procedure outlined in the example, corresponding para-(dialkylsulfamyl) -benzoic acids are obtained haw ing an alkyl group of the type disclosed for R;

and R in the general formula in column of the specification. Among the compounds pre-' pared by the method illustrated in Example III are those listed in Table B:

i The invention is-further illustrated by,- but; not restricted to, the following various dosage. forms of different compositions for administra tion by various routesm Example a.-Compressecl tablets.-l0,000, grams of lactose and 100,000 grams of the adjuvant, para-(di-n-propylsulfamyl) -benzoic acid, are uniformly mixed and wetted with suflicient. water to permit-its ready-granulation. 2,000 grams of dried cornstarch, 500 grams of karaya gum powder, 2,500 grams of talc, and. 1,000 grams of calcium stearat'e areintimately mixed and then mixed together uniformly with, the 110,000 grams of the mixture of the granulated adjuvant and lactose. The final mixture is then tableted (using inch die standard curvature punches) yielding 200,000 tablets of 0.58 gram each, and each containing 0.5 gram of theyad juvant. i l By replacing the quantity of the adjuvant-i-n the above example by the same quantity oi'any other selected adjuvant embraced within the scope of the general formula above, tablets of the same individual weight and same: content of any of the other adjuvantsare obtained., Measured amounts of the composition-of. Exe, ample a containing anyv selected adjuyant, or merely the adjuvant alone, can be filled into; hard gelatine, telescopic capsules, each holding. 0.5 gram of adjuvant. ,1 r Alternately, 'the selected adjuvant may be homogeneously dispersed in an equal quantity of corn oil, and the composition encapsulatedin, known manner. in soft, elastic sheet gelatin," hermetically sealed capsules each co n'taining one gram of the adjuvant -oil composition. j Example p.- mpuze.1o xkii sfl or, the s; juvant, para (di npropylsulfamyl)" benzoic acid, are suspended in very nearly 5,0 litersoi distilled watenand l ltil grams of sodium'l'i'y droxide are 'addedito help in theydissolutionjof the adjuvant'."' 390 grams'of mondpotassium phosphate are added and distilled watergadded to make the volume of solution up to 50jliters (pH is about 7.4); The solution] is then filled into ampulsfor 5 cc. liquid content each, which are then flame' sealed and autoclaved at- 15 pounds pressure for 20 minutes. v Example c.Compressed tablet ffcontamifiy penicillin-10,000 grams of lactose are mixed' with 100,000 grams of the adjuvant, para(dienprDylsulfamyD-benzoic acid, and granulated as in Example a; 3375 grams of sodium penicillin (-1630 units per mg), 2625 grams dried cornstarch, 500 grams karaya gum powder, 2500 grams talc and 1000 grams calcium, stearate are mixed together in an atmosphere controlled at 10% relative humidity at, 21 0., and then under the same conditions mixed with the granulation of the adjuvant and the lactose and tableted with the same die as in Example a yielding 200,000 tablets weighing 0.6 gram and each containing 0.5 gram of adjuvant and 25,000 units penicillin (plus 10% excess).

Any other selected adjuvant may replace the adjuvant of Example b in equal amount to obtain tablets of the same weight and same content of any of the other adjuvants.

Example cZ.-Dry filled capsule with penicillin-Under atmosphere controlled as in Example c, 25 kilos of the adjuvant, para-(di-npropylsulfamyD-benzoic acid, 850 g'rams'of crystalline penicillin sodium (as used'above), and 150 grams of dried cornstarch are intimately and uniformly mixed and the mixture filled into capsules, yielding 50,000 capsules, each holdmg 0.52 gram of mixture containing 0.5 gram of adjuvantand 25,000 units penicillin (plus 10% excess). 7

Example e.Soft elastic capsule with penicillin.*-Under atmosphere controlled as in Example c, 1.69 kilos of the same crystalline penicillin sodium are homogeneously dispersed in 48.31 kilos of corn oil and 50 kilos of the adjuvant, para- (di-n-propylsulfamyl)-benzoic acid, similarly dispersed in the oil, and the resulting composition encapsulated in known manner in soft, elastic, "sheet gelatin, hermetically sealed capsules, yielding 100,000 capsules, each holding one gram net of the composition and containing 0.5 gram-of adjuvant with 25,000 units penicillin (plus 10% excess). 7

Example f.Flame-sealed ampul filled with penicillin- 42.5 kilos of the adjuvant, para-(din-propylsulfamyl)-benzcic acid, are stirred into very nearly liters of sterile, pyrogen-free, distilled water and 1831 grams of sodium hydroxideare added to aid in the dissolution of the adjuvant. Then 390 grams of monopotassium phosphate are added and, under atmosphere conditions as in Example 0, 169 grams of the same crystalline penicillin sodium are added and stirred into solution andsufiicient water added to bring the total volume of solution to 30 liters. 12 cc. of this solution are then filled into each of the required number of 20 cc. total volume ampul-vials. The contents of the vials are then quickly frozen by rotating them in a bath of methyl Cellosolve chilled with Dry Ice to -70 C., and desiccated under high vacuum for 48 hours by'the method and apparatus as in United. States Patent No. 2,353,985 and rubber stoppers inserted in the neck of each of the contatiners while the vacuum is still being maintained. The vacuum is then broken and the containers removedfrom the apparatus and the extension'of the glass neck beyond the top of the. stoppers is flame-sealed. The contents of the flame-sealed ampul-vial are then restored with sterile, pyrogen-free, distilled water shortly before the product is to beused. When thus restored to 20 cc. liquid volume, the resulting solution is bufiered at pH 7.4. and contains 100,000 units penicillin (plus the 10% excess) and 25% of the adjuvant.

I abandoned.

persion of the white wax. While this mixture is still sufficiently liquid, and under atmosphere conditions as in Example 0, 10 kilos of the ad juvant, para-(di-mpropylsulfamyl) -benzoic acid, and 1873 grams of calcium penicillin (734 units/ mg.) are added and the mixture stirred to homogeneity. Each cc. of the resulting oil suspension,

contains 25,000 units of penicillin (plus 10% excess) and 0.2 gram of adjuvant. It is put'up in flame-sealed ampuls containing. suitable vol-- ume of the suspension which is as stable as the ordinary penicillin in peanut oil preparations.

While each, of the preceding Examples a throughg contains its respective specific adjuvant, each of them may be prepared with any othersuitable, effective adjuvanafor example, any other adjuvants embraced by the general formula above.

In addition, in those compositions containing penicillin, it is advisable, in accordance with r customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the label claimed quantity in accordance An excess of penicillin with present practice. 4 introduces no difiiculty save its cost. The pen-- icillin used may be any of the forms available.

for use, such as the calcium, sodium, potassium, procaine, and the like salts of amorphous or crystalline penicillin.

The quantity per dose of adjuvant and penicillin will depend upon the blood level and duration of action required for the particular condition encountered in each case. An advantageous ratio of adjuvant to penicillin per tablet or capsule is about one-half gram of the selected adjuvant to 25,000 to 200,000 units of penicillin.

The compositions of the invention may also include an antacid material, such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for; the purpose of neutralizing gastric acidity. The amount of antacid material is limited only to that which is desirable to use'in connection with penicillin or whichcan be physically incorporated in a tablet or capsule of suitable size for administration.

As to binders and lubricants used cel1ulose,mineral oil, propylene glycol, glycerin,

and the like, may be included in proportions tablets of this This application is a division of U. S.paten t application Serial No. 111,584,

r r I filed August 20', 1949, by myself and James I claim:

the general formula:

Alkyl w-so @coon 2- Alkyl in making; the tablets, such materials as lactose, corn starch, gum karaya, talc, calcium stearate, gelatin, ethyl Sprague, now' 9 and their non-toxic, water-soluble salts, wherein the alkyl radicals each contain at least 2 carbon atoms have a combined total of at least and no more than 8 carbon atoms.

2. A composition suitable for therapeutic use, comprising penicillin and an adjuvant which is a member of the group consisting of compounds having the general formula:

and their non-toxic, water-soluble salts, wherein R and R1 respectively are alkyl radicals; the alkyl radicals represented by R and R1 each contain at least 2 carbon atoms and have a combined total of at least 5 and no more than 8 carbon atoms, the quantity of adjuvant and penicillin in the composition being in the ratio of 0.5 gram of adjuvant to from 25,000 to 200,000 units of penicillin.

3. Para (di-n-propylsulfamyl) -benzoic acid having the formula n-Propyl N-soOo OOH n-Propyl 4. Para. (di n butylsulfamyl) -benzoic acid having the formula n-Butyl n-Butyl 5. Para (di isopropylsulfamyl) -benzoic acid having the formula Isopropyl Isopropvl 10 6. Para (di is'obutylsulfamyl) -benzoic acid having the formula Isobutyl /NS 000 0 0H Isobutyl 7. Para (di sec-butylsulfamyl) -benzoic acid having the formula sec-B utyl sec-B utyl CHARLES S. MILLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,162,211 Andersen June 13, 1939 2,223,916 Martin Dec. 3, 1940 2,229,744 Kern Jan. 28, 1941 OTHER REFERENCES 

1. A SULFAMYLBENZOIC ACID WHICH IS A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULA: 